Matrine-triazole derivative and synthetic method thereof

Abstract

The synthesis method comprises the following steps: weighing lithium diisopropylamide, adding the lithium diisopropylamide into a round-bottom flask, weighing matrine, dissolving the matrine in anhydrous tetrahydrofuran, weighing 3-propargyl bromide, slowly adding the matrine and the 3-propargyl bromide into a reaction system, drying, filtering, carrying out rotary evaporation to obtain a yellow oily crude product, and carrying out silica gel column chromatography purification to obtain the matrine-triazole derivative. Filtering to obtain 14-(propargyl) matrine (3); (3) dissolving a compound A and thiophene-2-cuprous formate in a toluene solution, sequentially adding a compound A and thiophene-2-cuprous formate, stirring at a constant speed, after the reaction is finished, adding water and dichloromethane for extraction, combining organic phases, filtering, carrying out reduced pressure distillation to obtain a green solid crude product, and carrying out silica gel column chromatography purification to obtain the matrine-triazole derivative. According to the matrine-triazole derivative and the synthesis method thereof, matrine is used as a lead compound to synthesize a 1, 2, 3-triazole structure-containing modifier with anti-tumor activity, and the 1, 2, 3-triazole structure-containing modifier is used as a medicine for screening in the medical field.

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, in particular to matrine-triazole derivatives and synthesis methods thereof. Background Art

[0002] Matrine is an alkaloid made by extracting the dried roots, plants and fruits of the leguminous plant Sophora flavescens through organic solvents such as ethanol. Matrine-type alkaloids belong to quinolizidine analogs and are composed of matrine, allomatrine, sophorocarpine, sophoridine, oxymatrine, sophoramine, sophorol, etc. And it has many biological activities and therapeutic properties. For example, matrine exhibits a variety of effective effects, including anti-inflammatory, antiviral, anti-tumor, anti-parasitic, antimicrobial, immunosuppressive, neuroprotective and cardioprotective effects. Pharmacological studies have found that matrine has a wide range of biological effects, including diuretic, anti-pathogen, anti-hepatitis virus and anti-cancer activities. Among them, anti-cancer activity studies have shown that matrine has an inhibitory effect on the proliferation of vascular endothelial cells induced by lung cancer and gastric cancer cells, with small side effects and low toxicity, indicating that matrine may become a therapeutic drug for preventing and treating tumor metastasis.

[0003] Heterocyclic compounds have special biological activities, especially nitrogen-containing heterocyclic compounds are widely used in the pharmaceutical industry. The addition of heterocyclic structural groups to certain drug precursors can often enhance biological activity. Triazole heterocyclic structures are indispensable active fragments in the field of drug design and synthesis, including benzotriazole, 1,2,3-triazole, 1,2,4-triazole and triazolopyrimidine, which are extremely important nitrogen heterocyclic pharmacophores. 1,2,3-triazole is rich in electrons and can bind to various targets, thereby producing a variety of biological activities, such as anti-tumor, antibacterial, anti-inflammatory, etc., and is widely used in the medical field. By introducing 1,2,3-triazole active fragments into matrine, the lipid solubility and anti-tumor activity of matrine are improved, thereby obtaining potential matrine derivatives. Summary of the invention

[0004] The purpose of the present invention is to provide a matrine-triazole derivative and a synthesis method thereof, and to use matrine as a lead compound to synthesize a 1,2,3-triazole structure-modified compound with anti-tumor activity for screening as a drug in the medical community.

[0005] To achieve the above object, the present invention provides a method for synthesizing a matrine-triazole derivative, comprising the following steps:

[0006] Step 1: In an ice bath and under nitrogen protection, lithium diisopropylamide (LDA) was weighed and added to a round-bottom flask, and stirred at a uniform speed. Matrine was weighed and dissolved in 80 mL of anhydrous tetrahydrofuran, and slowly added to the reaction system. After stirring for 1 h, 3-bromopropyne was weighed and slowly added to the reaction system. The mixture was stirred at room temperature for 5 h. Methanol:ethyl acetate=1:15 was used as the developing solvent. After TLC detection of the reaction was completed, the reaction system was closed, the reaction apparatus was dismantled, saturated NaHCO3 solution 150 mL was added to quench lithium diisopropylamide, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography with an eluent polarity of methanol:ethyl acetate=1:30 to obtain a white flocculent solid, namely 14-(propargyl)matrine (3);

[0007] Step 2: The 14-(propargyl)matrine (3) prepared in step 1 was dissolved in 3 mL of toluene solution, and compound A and 0.1396 mmol of cuprous thiophene-2-carboxylate were added in sequence. The mixture was stirred at a constant speed and reacted at room temperature for 3 h. The reaction progress was monitored by TLC plate. The developing solvent polarity was methanol: dichloromethane = 1:15. After the reaction was completed, water and dichloromethane were added for extraction. The organic phases were combined, filtered, and distilled under reduced pressure to obtain a green solid crude product. The product was purified by silica gel column chromatography. The eluent polarity was methanol: dichloromethane = 1:30 to obtain a white powdery solid, which was the matrine-triazole derivative.

[0008] Preferably, in step 1, the amount of lithium diisopropylamide added is 12 mL, the amount of matrine added is 20 mmol, and the amount of 3-bromopropyne added is 4 times that of matrine.

[0009] Preferably, in step 2, the amount of 14-(propargyl)matrine (3) added is 0.698 mmol, and the amount of compound A added is 1.047 mmol.

[0010] Preferably, in step 2, the synthesis method of compound A is:

[0011] Take trimethylsilane and place it in a 50mL round-bottom flask, add 8mL of hexamethylphosphoric acid triamide (HMPA) solution, drop compound B, and keep at 70°C overnight. Use petroleum ether as the developing solvent and monitor the reaction on a TLC plate. After the reaction is completed, cool to room temperature, remove the solvent by distillation under reduced pressure, add 100mL of water and dichloromethane to repeatedly extract the reaction system, combine the organic phases, dry over anhydrous Na2SO4, filter, rotary evaporate, and purify by silica gel column chromatography. The eluent polarity is ethyl acetate: petroleum ether = 1:100 to obtain a colorless transparent liquid.

[0012] Preferably, compound B is one of 4-fluorobenzyl bromide, 3-fluorobenzyl bromide, 2-fluorobenzyl bromide, 4-chlorobenzyl bromide, 3-chlorobenzyl bromide, 2-chlorobenzyl bromide, 4-bromobenzyl bromide, 3-bromobenzyl bromide, 2-bromobenzyl bromide, 4-methylbenzyl bromide, 4-tert-butylbenzyl bromide, 4-propylbenzyl bromide, 4-isopropylbenzyl bromide, 4-trifluoromethylbenzyl bromide, 3-trifluoromethylbenzyl bromide, 2-trifluoromethylbenzyl bromide, 4-trifluoromethoxybenzyl bromide, 3-trifluoromethoxybenzyl bromide, 3-benzyloxybenzyl bromide, 4-bromomethylbiphenyl, benzyl bromide, 1-bromomethylnaphthalene, and 2-(bromomethyl)naphthalene.

[0013] Preferably, the amount of azidotrimethylsilane added is 7.9 mmol, and the amount of compound B added is 3.8 mmol.

[0014] The invention relates to matrine-triazole derivatives and synthesis methods thereof, and synthesized matrine-triazole derivatives.

[0015] Preferably, the matrine-triazole derivative has the following structural formula:

[0016]

[0017] The R group is one of 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-CH3, 4-C(CH3)3, 4-CH2CH2CH3, 4-CH(CH3)2, 4-CF3, 3-CF3, 2-CF3, 4-O-CF3, 3-O-CF3, 3-O-CH2-C6H6, 4-C6H6, and H.

[0018] The advantages and positive effects of the matrine-triazole derivatives and the synthesis method thereof of the present invention are:

[0019] 1. The present invention modifies the structure of the C-14 position of matrine. Under the electron-withdrawing effect of the carbonyl group, the carbonyl position is deprotonated to generate a carbon anion intermediate, which is then reacted with propyne bromide. Finally, a matrine derivative containing a 1,2,3-triazole structure is synthesized by a click reaction, in order to obtain a matrine derivative with high lipid solubility, high bioavailability, good pharmacological activity and less toxic and side effects. 24 matrine-triazole derivatives are synthesized respectively, and all the synthesized target compounds are 1 HNMR, 13 C-NMR structural characterization and confirmation, and finally the antitumor activity and cell apoptosis of the target compound were investigated.

[0020] 2. The present invention uses matrine as a lead compound to provide a 1,2,3-triazole structural modification with anti-tumor activity and a preparation method thereof, which can be screened as a drug by the medical community. The synthesis and anti-cancer activity research of such compounds have not been reported either at home or abroad.

[0021] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a graph showing the results of cell cycle detection of liver cancer cell HepG2 by matrine derivative 4k at different concentrations in the application example of the present invention, wherein A is blank, B is 8.5 μL in concentration, C is 17 μL in concentration, and D is 34 μL in concentration;

[0023] Figure 2 This is a graph showing the results of analyzing the effects of different concentrations of matrine derivative 4k on the cell cycle of liver cancer cells HepG2 in the application example of the present invention, wherein A is the statistical result of the blank group, B is the statistical result of the G0 / G1 phase, C is the statistical result of the S phase, and D is the statistical result of the G2 / M phase;

[0024] Figure 3 The test results of the effects of different concentrations of matrine derivative 4k on cell apoptosis in the application example of the present invention are shown;

[0025] Figure 4 The results of analysis of cell apoptosis in each group of application examples of the present invention are as follows;

[0026] Figure 5 This is a synthetic route for the matrine derivatives 4a-4x containing a triazole structure of the present invention. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is further described below through the accompanying drawings and embodiments.

[0028] Unless otherwise defined, the technical terms or scientific terms used in the present invention should have the common meanings understood by people with ordinary skills in the field to which the present invention belongs. Unless otherwise specified, the reagents involved in the present invention are all commercially available.

[0029] Example 1

[0030] Compound 2a: Synthesis of 4-fluorobenzyl azide:

[0031] Take trimethylsilyl azide (900 mg, 7.8 mmol) and place it in a 50 mL round-bottom flask, add 8 mL of hexamethylphosphoric acid triamide (HMPA) solution, drop 4-fluorobenzyl bromide (738.2 mg, 3.9 mmol), and incubate at 70 ° C overnight with petroleum ether as the developing solvent. The reaction is monitored by TLC plate. After the reaction is completed, cool to room temperature, distill under reduced pressure to remove the solvent, add 100 mL of water and dichloromethane (30 mL × 3 times) to repeatedly extract the reaction system, combine the organic phases, dry over anhydrous Na2SO4, filter, rotary evaporate, and purify by silica gel column chromatography. The eluent polarity is ethyl acetate: petroleum ether = 1:100 (V / V) to obtain 569.8 mg of colorless transparent liquid with a yield of 96.66%.

[0032] Compound 2b: Synthesis of 3-fluorobenzyl azide:

[0033] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 3-fluorobenzyl bromide (738.2 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 565.7 mg of colorless transparent liquid with a yield of 95.97%.

[0034] Compound 2c: Synthesis of 2-fluorobenzyl azide:

[0035] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 2-fluorobenzyl bromide (738.2 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 554.9 mg of colorless transparent liquid with a yield of 94.14%.

[0036] Compound 2d: Synthesis of 4-chlorobenzyl azide:

[0037] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-chlorobenzyl bromide (801.4 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 608.7 mg of colorless transparent liquid with a yield of 93.13%.

[0038] Compound 2e: Synthesis of 3-chlorobenzyl azide:

[0039] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 3-chlorobenzyl bromide (801.4 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 601.1 mg of colorless transparent liquid with a yield of 91.96%.

[0040] Compound 2f: Synthesis of 2-chlorobenzyl azide:

[0041] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 2-chlorobenzyl bromide (801.4 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 589.2 mg of colorless transparent liquid with a yield of 90.14%.

[0042] Compound 2g: Synthesis of 4-bromobenzyl azide:

[0043] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-bromobenzyl bromide (974.7 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 811.4 mg of colorless transparent liquid with a yield of 98.11%.

[0044] Compound 2h: Synthesis of 3-bromobenzyl azide:

[0045] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 3-bromobenzyl bromide (974.7 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 801.3 mg of colorless transparent liquid with a yield of 96.89%.

[0046] Compound 2i: Synthesis of 2-bromobenzyl azide:

[0047] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 2-bromobenzyl bromide (974.7 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 769.4 mg of colorless transparent liquid with a yield of 93.04%.

[0048] Compound 2j: Synthesis of 4-methylbenzyl azide:

[0049] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-methylbenzyl bromide (721.7 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 527.5 mg of colorless transparent liquid with a yield of 91.90%.

[0050] Compound 2k: Synthesis of 4-tert-butylbenzyl azide:

[0051] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-tert-butylbenzyl bromide (885.8 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 709.0 mg of colorless transparent liquid with a yield of 96.05%.

[0052] Compound 21: Synthesis of 4-propylbenzyl azide:

[0053] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-propylbenzyl bromide (776.4 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 628.8 mg of colorless transparent liquid with a yield of 92.01%.

[0054] Compound 2m: Synthesis of 4-isopropylbenzyl azide:

[0055] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-isopropylbenzyl bromide (776.4 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 648.3 mg of colorless transparent liquid with a yield of 94.86%.

[0056] Compound 2n: Synthesis of 4-trifluoromethylbenzyl azide:

[0057] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-trifluoromethylbenzyl bromide (932.2 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 635.9 mg of colorless transparent liquid with a yield of 81.06%.

[0058] Compound 2o: Synthesis of 3-trifluoromethylbenzyl azide:

[0059] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 3-trifluoromethylbenzyl bromide (932.2 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 610.0 mg of colorless transparent liquid with a yield of 77.76%.

[0060] Compound 2p: Synthesis of 2-trifluoromethylbenzyl azide:

[0061] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 2-trifluoromethylbenzyl bromide (932.2 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 583.8 mg of colorless transparent liquid with a yield of 74.42%.

[0062] Compound 2q: Synthesis of 4-trifluoromethoxybenzyl azide:

[0063] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-trifluoromethoxybenzyl bromide (994.6 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 730.4 mg of colorless transparent liquid with a yield of 86.24%.

[0064] Compound 2r: Synthesis of 3-trifluoromethoxybenzyl azide:

[0065] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 3-trifluoromethoxybenzyl bromide (994.6 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 746.4 mg of colorless transparent liquid with a yield of 88.13%.

[0066] Compound 2s: Synthesis of 3-benzyloxybenzyl azide:

[0067] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 3-benzyloxybenzyl bromide (1081.1 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 696.5 mg of colorless transparent liquid with a yield of 79.28%.

[0068] Compound 2t: Synthesis of 4-(azidomethyl)biphenyl:

[0069] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 4-bromomethylbiphenyl (963.8 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 506.9 mg of colorless transparent liquid with a yield of 62.11%.

[0070] Compound 2u: Synthesis of benzyl azide:

[0071] Using azidotrimethylsilane (900 mg, 7.8 mmol) and benzyl bromide (667.0 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 457.0 mg of colorless transparent liquid with a yield of 88.00%.

[0072] Compound 2v: Synthesis of (2-azidoethyl)benzene:

[0073] Using azidotrimethylsilane (900 mg, 7.8 mmol) and (2-bromoethyl)benzene (721.7 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 379.4 mg of colorless transparent liquid with a yield of 66.10%.

[0074] Compound 2w: Synthesis of 1-azidomethylnaphthalene:

[0075] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 1-bromomethylnaphthalene (862.3 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 548.6 mg of colorless transparent liquid with a yield of 76.78%.

[0076] Compound 2x: Synthesis of 2-azidomethylnaphthalene:

[0077] Using azidotrimethylsilane (900 mg, 7.8 mmol) and 2-(bromomethyl)naphthalene (862.3 mg, 3.9 mmol) as raw materials, the synthesis method was consistent with the synthesis of 4-fluorobenzyl azide to obtain 446.9 mg of colorless transparent liquid with a yield of 62.54%.

[0078] Example 2

[0079] Matrine-triazole derivatives and their synthesis methods, such as Figure 5 As shown, the following steps are included:

[0080] Step 1: In an ice bath and under nitrogen protection, 12 mL of lithium diisopropylamide (LDA) was added to a round-bottom flask and stirred at a uniform speed. 20 mmol of matrine was weighed and dissolved in 80 mL of anhydrous tetrahydrofuran and slowly added to the reaction system. After stirring for 1 h, 80 mmol of 3-bromopropyne was weighed and slowly added to the reaction system. The mixture was stirred at room temperature for 5 h. Methanol:ethyl acetate=1:15 was used as the developing solvent. After TLC detection of the reaction was completed, the reaction system was closed and the reaction apparatus was dismantled. 150 mL of saturated NaHCO3 solution was added to quench the lithium diisopropylamide. The mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography with the eluent polarity of methanol:ethyl acetate=1:30 to obtain a white flocculent solid, i.e. 14-(propargyl)matrine (3).

[0081] 1 HNMR(600MHz,DMSO-d6)δ4.12(dd,J=12.2,4.1Hz,1H),3.86–3.82(m,1H),2.96(t,J=12.4Hz,1H),2.80–2.71(m, 3H),2.47–2.46(m,2H),2.38–2.33(m,1H),2.08(s,1H),1.88–1.76(m,7H),1.62–1.42(m,6H),1.37–1.27(m,3H). 13 CNMR(150MHz,DMSO-d6)δ168.87,83.12,72.78,64.03,57.19,57.13,53.22,42.77,41 .16,40.42,36.45,27.98,26.62,22.19,22.15,21.24,21.12,20.70.MSm / zcalcdforC 18 H 26 N2O[M+H] + 287.21, found 287.13.

[0082] Step 2: 0.698 mmol of 14-(propargyl)matrine (3) prepared in step 1 was dissolved in 3 mL of toluene solution, and 1.047 mmol of compound A and 0.1396 mmol of cuprous thiophene-2-carboxylate were added in sequence. The mixture was stirred at a constant speed and reacted at room temperature for 3 h. The reaction progress was monitored by TLC plate. The developing solvent polarity was methanol: dichloromethane = 1:15. After the reaction was completed, water and dichloromethane were added for extraction. The organic phases were combined, filtered, and distilled under reduced pressure to obtain a green solid crude product. The product was purified by silica gel column chromatography. The eluent polarity was methanol: dichloromethane = 1:30 to obtain a white powdery solid, which was the matrine-triazole derivative.

[0083] Substitute the compound 2a-2x synthesized in Example 1, that is, compound A, into the matrine-triazole derivative and its synthesis method to synthesize matrine-triazole derivatives (4a-4x) respectively.

[0084] Matrine-triazole derivative 4a: Synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0085] 14-(Propargyl)matrine (3) (200 mg, 0.698 mmol) was dissolved in 3 mL of toluene solution, and 4-fluorobenzyl azide (compound 2a, 1.047 mmol) and cuprous thiophene-2-carboxylate (0.1396 mmol) were added in sequence, stirred at a constant speed, reacted at room temperature for 3 h, and the reaction progress was monitored by TLC plate. The developing solvent polarity was methanol: dichloromethane = 1:15 (containing 1 / 1000 ammonia water). After the reaction was completed, a certain amount of water and dichloromethane (30 mL × 3 times) were added for extraction, and the organic phases were combined, filtered, and distilled under reduced pressure to obtain a green solid crude product, which was purified by silica gel column chromatography. The eluent polarity was methanol: dichloromethane = 1:30 (V / V) to obtain 240.0 mg of a white powdery solid with a yield of 78.55%. Melting point: 171.41-172.07°C.

[0086] 1 HNMR (600MHz, DMSO-d6) δ7.71 (s, 1H), 7.35–7.33 (m, 2H), 7.17 (t, J = 8.8Hz, 2H), 5. 50(q,J=14.8Hz,2H),4.08(dd,J=12.2,4.1Hz,1H),3.72–3.69(m,1H),2.97–2.93( m,1H),2.88–2.84(m,2H),2.66(t,J=13.5Hz,2H),2.50–2.48(m,1H),1.80–1.73(m ,3H),1.71–1.60(m,3H),1.55–1.46(m,3H),1.41–1.23(m,6H),1.11–0.98(m,2H).13 CNMR (150MHz, DMSO-d6) δ169.72, 162.28 (d, J = 243Hz), 145.51, 132.96 (d, J = 3.0Hz), 130.57 (d, J = 8.4Hz), 123.11, 116.02 (d, J = 21.4H z),63.76,57.17,57.10,53.08,52.24,42.64,41.54,41.25,36.18,27.92,27.53,26.47,22.16,21.85,21.22,20.64.MSm / zcalcdforC 25 H 32 FN5O[M+H] + 438.26, found 438.28.

[0087] Matrine-triazole derivative 4b: Synthesis of 14-[1-(3-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0088] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 3-fluorobenzyl azide (2b, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 181.1 mg of white powdery solid with a yield of 59.27%. Yield: 59.17%; melting point: 155.46-157.13°C.

[0089] 1 HNMR(600MHz,DMSO-d6)δ7.77(s,1H),7.42–7.38(m,1H),7.17–7.14(m,1H),7.11 –7.08(m,2H),5.55(q,J=15.0Hz,2H),4.10(dd,J=12.3,4.2Hz,1H),3.74–3.70(m ,1H),2.99–2.95(m,1H),2.90–2.85(m,2H),2.67(t,J=14.2Hz,2H),2.52–2.50(m ,1H),1.79–1.61(m,6H),1.56–1.47(m,3H),1.42–1.24(m,6H),1.12–1.02(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.73,162.61(d,J=242.7Hz),145.52,139.42(d,J= 7.2Hz),131.24(d,J=8.0Hz),124.35(d,J=2.2Hz),123.44,115.43(d,J=21.0H z),115.07(d,J=21.7Hz),63.73,57.15,57.08,53.08,52.33,42.65,41.54,41 .28,36.22,27.92,27.52,26.46,22.17,21.86,21.22,20.64.MSm / zcalcdforC 25 H 32 FN5O[M+H] + 438.26, found 438.27.

[0090] Matrine-triazole derivative 4c: Synthesis of 14-[1-(2-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0091] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 2-fluorobenzyl azide (compound 2c, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 215.3 mg of white powdery solid with a yield of 70.47%. Melting point: 152.32-153.91°C.

[0092] 1 HNMR(600MHz,DMSO-d6)δ7.71(s,1H),7.40–7.37(m,1H),7.27(t,J=7.4Hz,1H), 7.22–7.15(m,2H),5.57(t,J=16.1Hz,2H),4.09(dd,J=12.2,3.8Hz,1H),3.73–3. 70(m,1H),2.93–2.86(m,3H),2.66(t,J=14.1Hz,2H),2.50–2.47(m,1H),1.86(s, 1H),1.81–1.69(m,4H),1.64–1.42(m,5H),1.40–1.23(m,5H),1.14–1.10(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.78,160.51(d,J=245.5Hz),145.44,131.10(d,J=8. 0Hz),131.03(d,J=3.3Hz),125.22(d,J=3.3Hz),123.42(d,J=14.6Hz),123.29,11 6.04(d,J=20.6Hz),63.84,57.17,57.10,53.12,47.11(d,J=3.7Hz),42.59,41.55 ,41.38,36.15,27.97,27.48,26.53,22.22,21.92,21.24,20.67.MSm / zcalcdforC 25 H 32 FN5O[M+H] + 438.26, found 438.29.

[0093] Matrine-triazole derivative 4d: Synthesis of 14-[1-(4-chlorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0094] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-chlorobenzyl azide (compound 2d, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 270.0 mg of a white powdery solid with a yield of 85.17%; melting point: 197.56-198.74°C.

[0095] 1 HNMR(600MHz,DMSO-d6)δ7.70(s,1H),7.43(d,J=8.2Hz,2H),7.32(d,J=8.2Hz,2H),5.54 (q,J=14.9Hz,2H),4.09(dd,J=12.1,4.0Hz,1H),3.73–3.71(m,1H),3.05–3.01(m,1H),2 .90–2.83(m,2H),2.68(t,J=13.4Hz,2H),2.50(s,1H),1.83–1.66(m,6H),1.56–1.47(m, 3H),1.42–1.25(m,5H),1.17(d,J=11.2Hz,1H),1.10–1.04(m,1H),0.89(d,J=9.8Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.67,145.54,135.72,133.26,130.24,129.25,123.20,63.62,57.13,57.05, 53.06,52.21,42.74,41.51,41.13,36.25,27.89,27.53,26.42,22.09,21.76,21.21,20.63.MSm / zcalcd forC 25 H 32 ClN5O[M+H] + 454.23, found 454.28.

[0096] Matrine-triazole derivative 4e: Synthesis of 14-[1-(3-chlorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0097] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 3-chlorobenzyl azide (compound 2e, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 183.9 mg of a white powdery solid with a yield of 58.01%; melting point: 147.88-148.74°C.

[0098] 1 HNMR(600MHz,DMSO-d6)δ7.76(s,1H),7.38–7.35(m,3H),7.23–7.21(m,1H),5.54 (q,J=14.9Hz,2H),4.09(dd,J=12.2,4.1Hz,1H),3.72–3.69(m,1H),2.98–2.95(m, 1H),2.88–2.84(m,2H),2.65(t,J=13.7H2H),2.50–2.47(m,1H),1.79–1.76(m,3H) ,1.72–1.46(m,6H),1.41–1.24(m,6H),1.12–1.07(m,1H),0.99(d,J=10.0Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.72,145.53,139.08,133.76,131.09,128.58,128.21,126.99,123.43,63.68,57.15 ,57.07,53.06,52.24,42.65,41.53,41.28,36.22,27.94,27.55,26.46,22.17,21.87,21.24,20.66.MSm / zcalcd forC 25 H 32 ClN5O[M+H] + 454.23,found454.22.

[0099] Matrine-triazole derivative 4f: Synthesis of 14-[1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0100] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 2-chlorobenzyl azide (compound 2f, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 160.7 mg of brown-yellow solid with a yield of 50.69%; melting point: 78.68-79.57°C.

[0101] 1 HNMR(600MHz,DMSO-d6)δ7.66(s,1H),7.49(d,J=7.9Hz,1H),7.39(t,J=7.6Hz,1H),7.33(t,J=7.5H z,1H),7.20(d,J=7.6Hz,1H),5.62(q,J=15.2Hz,2H),4.09(dd,J=12.2,4.1Hz,1H),3.75–3.72(m,1 H),2.97–2.94(m,1H),2.90–2.86(m,2H),2.68(t,J=14.5Hz,2H),2.53–2.50(m,1H),1.88(s,1H),1 .81(t,J=11.7Hz,2H),1.75–1.64(m,3H),1.59–1.46(m,3H),1.41–1.25(m,6H),1.17–1.13(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.75,145.37,133.76,133.11,130.96,130.70,130.12,128.12,123.38,63.86,57. 16,57.08,53.14,50.92,42.63,41.56,41.33,36.18,27.95,27.45,26.53,22.21,21.86,21.22,20.66.MSm / zc alcdforC 25 H 32 ClN5O[M+H] + 454.23,found454.23.

[0102] Matrine-triazole derivative 4g: Synthesis of 14-[1-(4-bromobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0103] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-bromobenzyl azide (compound 2 g, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 259.0 mg of white solid with a yield of 74.41%; melting point: 177.18-178.43°C.

[0104] 1 HNMR(600MHz,DMSO-d6)δ7.69(s,1H),7.57(d,J=8.2Hz,2H),7.26(d,J=8.2Hz,2H),5.52(q,J=14.8 Hz,2H),4.09(dd,J=12.1,4.0Hz,1H),3.73–3.70(m,1H),3.07–3.03(m,1H),2.89–2.82(m,2H),2.6 8(t,J=13.4Hz,2H),2.51(s,1H),1.85–1.81(m,2H),1.73–1.62(m,4H),1.56–1.55(m,2H),1.48(d, J=13.3Hz,1H),1.42–1.32(m,4H),1.26(d,J=13.0Hz,1H),1.15–1.05(m,2H),0.85(d,J=9.9Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.64,145.53,136.13,132.18,130.54,123.19,121.91,63.57,57.10,57.01,53 .04,52.26,42.76,41.51,41.09,36.28,27.89,27.54,26.41,22.07,21.73,21.21,20.63.MSm / zcalcdforC 25 H 32 BrN5O[M+H] + 498.18, found 498.19.

[0105] Matrine-triazole derivatives 4h: Synthesis of 14-[1-(3-bromobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0106] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 3-bromobenzyl azide (compound 2h, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 272.9 mg of a white crystalline solid with a yield of 78.40%; melting point: 197.18-198.43°C.

[0107] 1 HNMR(600MHz,DMSO-d6)δ7.76(s,1H),7.51(d,J=7.5Hz,2H),7.30(t,J=7.8Hz,1H),7.26( d,J=7.7Hz,1H),5.53(q,J=14.9Hz,2H),4.08(dd,J=12.3,4.1Hz,1H),3.72–3.68(m,1H),2 .98–2.94(m,1H),2.88–2.84(m,2H),2.65(t,J=13.7Hz,2H),2.52–2.49(m,1H),1.79–1.7 6(m,3H),1.71–1.52(m,5H),1.46(d,J=13.2Hz,1H),1.40–1.22(m,6H),1.12–0.97(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.72,145.53,139.31,131.48,131.37,131.11,127.37,123.42,122.36,63.66,57.14,5 7.07,53.06,52.18,42.66,41.52,41.28,36.22,27.95,27.56,26.46,22.18,21.87,21.25,20.68.MSm / zcalcdforC 25 H 32 BrN5O[M+H] + 498.18, found 498.19.

[0108] Matrine-triazole derivative 4i: Synthesis of 14-[1-(2-bromobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0109] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 2-bromobenzyl azide (compound 2i, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 211.9 mg of a transparent oily substance with a yield of 60.88%; melting point: 53.79-54.72°C.

[0110] 1 HNMR(600MHz,DMSO-d6)δ7.67(d,J=7.9Hz,1H),7.64(s,1H),7.38(t,J=7.4Hz,1H),7.32–7.30(m,1H), 7.16(dd,J=7.6,1.3Hz,1H),5.61(q,J=15.2Hz,2H),4.09(dd,J=12.2,4.2Hz,1H),3.76–3.73(m,1H),2 .98–2.95(m,1H),2.91–2.87(m,2H),2.68(t,J=14.7,2H),2.54–2.50(m,1H),1.89(s,1H),1.83–1.79( m,2H),1.76–1.64(m,3H),1.57–1.54(m,2H),1.49–1.42(m,2H),1.39–1.26(m,5H),1.19–1.14(m,2H). 13CNMR(150MHz,DMS O-d6)δ169.73,145.39,135.35,133.41,130.97,130.89,128.67,123.40,123.35,63.87,57.17,57.10,53 .26,53.15,42.64,41.58,41.32,36.19,27.97,27.46,26.55,22.22,21.87,21.24,20.67.MSm / zcalcdforC 25 H 32 BrN5O[M+H] + 498.18,found498.21.

[0111] Matrine-triazole derivative 4j: Synthesis of 14-[1-(4-methylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0112] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-methylbenzyl azide (compound 2j, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 227.9 mg of a white powdery solid with a yield of 75.27%; melting point: 169.92-171.18°C.

[0113] 1 HNMR(600MHz,DMSO-d6)δ7.64(s,1H),7.15(q,J=8.0Hz,4H),5.44(q,J=14.7Hz,2H),4. 08(dd,J=12.2,4.1Hz,1H),3.72–3.68(m,1H),3.00–2.97(m,1H),2.88–2.82(m,2H),2.6 7(t,J=13.3Hz,2H),2.51–2.48(m,1H),2.28(s,3H),1.77(t,J=11.5Hz,2H),1.70–1.60( m,4H),1.55–1.30(m,7H),1.25–1.19(m,2H),1.09–1.04(m,1H),0.93(d,J=10.0Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.71,145.41,137.68,133.70,129.76,128.28,122.99,63.66,57.19,57.12,53.07 ,52.83,42.69,41.52,41.13,36.19,27.91,27.54,26.44,22.12,21.78,21.32,21.21,20.63.MSm / zcalcdforC 26 H 35 N5O[M+H] + 434.29,found434.28.

[0114] Matrine-triazole derivative 4k: Synthesis of 14-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0115] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-tert-butylbenzyl azide (compound 2k, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 185.0 mg of a transparent solid with a yield of 55.70%; melting point: 65.78-66.78°C.

[0116] 1 HNMR (600MHz, DMSO-d6) δ7.76 (s, 1H), 7.35–7.34 (m, 2H), 7.18 (d, J = 8.3Hz, 2H), 5. 47(s,2H),4.12(dd,J=12.2,3.7Hz,1H),3.74–3.71(m,1H),2.97–2.93(m,1H),2.91 –2.86(m,2H),2.67(t,J=14.0Hz,2H),2.51–2.50(m,1H),1.83–1.77(m,3H),1.73–1 .61(m,3H),1.56–1.48(m,3H),1.42–1.29(m,5H),1.24(s,10H),1.11–1.07(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.76,150.79,145.35,133.81,127.93,125.85,123.27,63.78,57.15,57.09,53.07,52 .68,42.60,41.57,41.29,36.22,34.72,31.56,28.00,27.57,26.52,22.19,21.91,21.23,20.66.MSm / zcalcdforC 29 H 41 N5O[M+H] + 476.33, found 476.35.

[0117] Matrine-triazole derivative 4l: Synthesis of 14-[1-(4-propylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0118] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-propylbenzyl azide (compound 21, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 241.3 mg of brown-yellow powdery solid with a yield of 74.85%; melting point: 116.08-116.80°C.

[0119] 1 HNMR(600MHz,DMSO-d6)δ7.69(s,1H),7.15(q,J=8.1Hz,4H),5.46(q,J=14.8Hz,2H),4.0 9(dd,J=12.2,4.2Hz,1H),3.70–3.69(m,1H),2.98–2.94(m,1H),2.88–2.84(m,2H),2.66( t,J=13.8Hz,2H),2.53–2.49(m,3H),1.78–1.75(m,3H),1.71–1.60(m,3H),1.57–1.52(m, 4H),1.47(d,J=13.6Hz,1H),1.41–1.22(m,6H),1.09–0.99(m,2H),0.85(t,J=7.3Hz,3H). 13CNMR(150MHz,DMSO-d6)δ169.72,145.39,142.34,134.02,129.08,128.18,123.12,63.70,57.18,57.11,53.07,52.82 ,42.65,41.55,41.20,37.50,36.19,27.94,27.54,26.47,24.46,22.16,21.83,21.23,20.65,14.11.MSm / zcalcdforC 28 H 39 N5O[M+H] + 462.32,found462.32.

[0120] Matrine-triazole derivative 4m: Synthesis of 14-[1-(4-isopropylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0121] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-isopropylbenzyl azide (compound 2m, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 267.3 mg of a white powdery solid with a yield of 82.92%; melting point: 164.75-165.65°C.

[0122] 1 HNMR(600MHz,DMSO-d6)δ7.75(s,1H),7.21(q,J=7.9Hz,4H),5.93(t,J=15.9 Hz,2H),4.12(dd,J=12.1,3.7Hz,1H),3.76–3.72(m,1H),2.98–2.95(m,1H),2 .92–2.87(m,3H),2.70(t,J=13.7Hz,2H),2.50(s,1H),1.83–1.64(m,6H),1. 58–1.50(m,3H),1.45–1.26(m,6H),1.19(d,J=6.9Hz,6H),1.14–1.08(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.76,148.56,145.36,134.15,128.23,127.06,123.24,63.73,57.13,57.07,53 .08,52.77,42.63,41.53,41.25,36.20,33.56,27.97,27.53,26.49,24.30,22.16,21.86,21.21,20.63.MS m / zcalcdforC 28 H 39 N5O[M+H] + 462.32, found 462.33.

[0123] Matrine-triazole derivative 4n: Synthesis of 14-[1-(4-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0124] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-trifluoromethylbenzyl azide (compound 2n, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 183.7 mg of a white powdery solid with a yield of 53.96%; melting point: 227.91-229.73°C.

[0125] 1 HNMR(600MHz,DMSO-d6)δ7.79(s,1H),7.75(d,J=8.0Hz,2H),7.49(d,J=7.9Hz,2H),5.7 3(q,J=15.2Hz,2H),4.10(dd,J=12.2,3.9Hz,1H),3.73–3.72(m,1H),3.04–3.00(m,1H) ,2.90–2.86(m,2H),2.68(t,J=13.4Hz,2H),2.50(s,1H),1.79–1.68(m,6H),1.59–1.48 (m,3H),1.43–1.31(m,4H),1.27–1.21(m,2H),1.09–1.05(m,1H),0.95(d,J=9.8Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.68,145.58,141.41,129.11(q,J=31.5Hz),128.96,126.14(q,J=3.8Hz),124.58(q,J=272.25Hz),123. 58,63.61,57.03,56.96,53.04,52.31,42.69,41.52,41.15,36.26,27.88,27.54,26.42,22.10,21.79,21.18,20.61.MSm / zcalcdfor C 26 H 32 F3N5O[M+H] + 488.26, found 488.26.

[0126] Matrine-triazole derivative 4o: Synthesis of 14-[1-(3-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0127] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 3-trifluoromethylbenzyl azide (compound 2o, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 147.5 mg of light yellow powdery solid with a yield of 43.32%; melting point: 149.32-150.38°C.

[0128] 1 HNMR(600MHz,DMSO-d6)δ7.82(s,1H),7.67(d,J=6.5Hz,2H),7.59–7.53(m,2H),5.64(q,J=15.2Hz,2H),4.08(dd,J=12.3,4.0Hz,1H) ,3.72–3.69(m,1H),2.95–2.84(m,3H),2.64(t,J=14.5Hz,2H),2.49(s,1H),1.77–1.52(m,8H),1.47–1.21(m,7H),1.10–1.04(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.74,145.61,138.15,132.34,130.34,129.90(q,J=31.5Hz),125.31(q,J=3.8Hz),124.94(q,J=3.8Hz),124.47(q,J=27 1.5Hz),123.53,63.74,57.12,57.04,53.06,52.28,42.58,41.54,41.34, 36.17,27.90,27.52,26.43,22.18,21.88,21.20,20.63.MSm / zcalcdforC 26 H 32 F3N5O[M+H] + 488.26, found 488.28.

[0129] Matrine-triazole derivative 4p: Synthesis of 14-[1-(2-trifluoromethylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0130] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 2-trifluoromethylbenzyl azide (compound 2p, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 265.7 mg of brown-yellow powdery solid with a yield of 78.04%; melting point: 140.72-141.18°C.

[0131] 1 HNMR(600MHz,DMSO-d6)δ7.78(d,J=7.7Hz,1H),7.67–7.63(m,2H),7.56(t, J=7.6Hz,1H),7.18(d,J=7.7Hz,1H),5.71(q,J=15.7Hz,2H),4.08(dd,J=12. 2,4.1Hz,1H),3.75–3.71(m,1H),2.97–2.86(m,3H),2.67(t,J=15.0Hz2H), 2.54–2.49(m,1H),1.82–1.64(m,6H),1.55–1.24(m,9H),1.15–1.11(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.74,145.55,134.24,133.53,130.80,129.37,127.08(q,J=30.1Hz),126.63(q,J=5.5Hz),123.62(q,J=272.6Hz),123 .62,63.84,57.15,57.08,53.12,49.82(q,J=3Hz),42.60,41.58,41.29, 36.20,27.93,27.45,26.50,22.19,21.84,21.20,20.64.MSm / zcalcdforC 26 H 32 F3N5O[M+H] + 488.26, found 488.28.

[0132] Matrine-triazole derivative 4q: Synthesis of 14-[1-(4-trifluoromethoxybenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0133] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-trifluoromethoxybenzyl azide (compound 2q, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 151.9 mg of white flocculent crystals with a yield of 43.20%; melting point: 183.49-184.45°C.

[0134] 1 HNMR(600MHz,DMSO-d6)δ7.80(s,1H),7.42–7.36(m,4H),5.59(q,J=15.0Hz,2H),4.12(dd,J=12.2,4.0Hz,1H),3.76–3.73(m,1H),2.99–2.95 (m,1H),2.92–2.88(m,2H),2.70(t,J=14.0Hz,2H),2.50(s,1H),1.82– 1.64(m,6H),1.58–1.50(m,3H),1.45–1.26(m,6H),1.14–1.05(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.74,148.46,145.53,136.16,130.27,123.44,121.66,120.50(q,J=254.9Hz),63.73,57.1 0,57.03,53.08,52.09,42.64,41.52,41.28,36.22,27.92,27.52,26.46,22.15,21.86,21.20,20.63.MSm / zcalcdforC 26 H 32 F3N5O2[M+H] + 504.25, found 504.28.

[0135] Matrine-triazole derivative 4r: Synthesis of 14-[1-(3-trifluoromethoxybenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0136] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 3-trifluoromethoxybenzyl azide (compound 2r, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 307.0 mg of a white powdery solid with a yield of 87.31%; melting point: 135.02-135.22°C.

[0137] 1 HNMR(600MHz, DMSO-d6)δ7.82(s,1H),7.49(t,J=8.2Hz,1H),7.32–7.26(m,3H),5.60(q,J=15.2Hz,2H),4.10(dd,J=12.2,4.0Hz,1H),3.74–3.71( m,1H),2.96–2.86(m,3H),2.67(t,J=14.4Hz,2H),2.52–2.50(m,1H),1.8 2–1.61(m,6H),1.56–1.34(m,6H),1.32–1.24(m,3H),1.15–1.07(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.74,148.94,145.57,139.45,131.23,127.23,123.53,120.90,120.62,120.48(q,J=255.1Hz),63. 75,57.13,57.06,53.07,52.17,42.60,41.55,41.33,36.19,27.91,27.50,26.45,22.17,21.85,21.21,20.64.MSm / zcalcdforC 26 H 32 F3N5O2[M+H] + 504.25, found 504.26.

[0138] Matrine-triazole derivative 4s: Synthesis of 14-[1-(3-benzyloxybenzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0139] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 3-benzyloxybenzyl azide (compound 2s, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 256.7 mg of yellow solid with a yield of 71.85%; melting point: 131.28-132.70°C.

[0140] 1 HNMR(600MHz,DMSO-d6)δ7.71(s,1H),7.40(d,J=7.4Hz,2H),7.34(t,J=7.5Hz,2H),7.28(t,J=7.2Hz,1H), 7.24(t,J=7.9Hz,1H),6.96–6.93(m,2H),6.81(d,J=7.6Hz,1H),5.21(q,J=14.8Hz,2H),5.03(t,J=12.4Hz ,2H),4.08(dd,J=12.2,4.0Hz,1H),3.70–3.67(m,1H),2.95–2.91(m,1H),2.88–2.83(m,2H),2.63(t,J=13 .38Hz,2H),2.49–2.48(m,1H),1.77–1.58(m,6H),1.52–1.43(m,3H),1.38–1.19(m,6H),1.10–1.02(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.76,159.03,145.45,138.18,137.29,130.34,128.88,128.33,128.12,123.30,120.57,114.95,114.53,69 .69,63.66,57.13,57.07,53.07,52.95,42.63,41.55,41.27,36.18,27.91,27.58,26.43,22.18,21.89,21.23,20.66.MSm / zcalcdforC 32 H 39 N5O2[M+H] + 526.31, found526.31.

[0141] Matrine-triazole derivative 4t: Synthesis of 14-[1-(4-(methyl)-biphenyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0142] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 4-(azidomethyl)biphenyl (compound 2t, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 314.0 mg of a white solid with a yield of 90.71%; melting point: 199.71-200.57°C.

[0143] 1 HNMR(600MHz,DMSO-d6)δ7.73–7.66(m,5H),7.44(t,J=7.3Hz,2H),7.37–7.33(m,3H),5.56(q,J=14.8Hz,2H),4.07(dd,J=12.0,3.5Hz,1H),3.70– 3.67(m,1H),3.03–3.0(m,1H),2.86–2.82(m,2H),2.60–2.51(m,3H),1.7 0–1.60(m,6H),1.54–1.43(m,3H),1.36–1.18(m,6H),1.06–0.92(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.68,145.51,140.14,139.78,135.88,129.41,128.89,128.12,127.34,127.09,123.20,63.49, 56.98,56.89,53.04,52.70,42.68,41.55,41.11,36.21,27.86,27.55,26.41,22.11,21.79,21.16,20.59.MSm / zcalcdforC 31 H 37 N5O[M+H] + 496.30, found 496.32.

[0144] Matrine-triazole derivative 4u: Synthesis of 14-[1-(benzyl)-1H-1,2,3-triazole-4-methyl]-matrine:

[0145] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and benzyl azide (compound 2u, 1.047 mmol) as raw materials, the synthesis method is consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 172.0 mg of light yellow oily substance with a yield of 58.57%Y; melting point: 150.40-152.12°C.

[0146] 1 HNMR(600MHz,DMSO-d6)δ7.72(s,1H),7.33–7.28(m,3H),7.24(d,J=7.1Hz,2H ),5.50(q,J=14.9Hz,2H),4.08(dd,J=12.2,4.0Hz,1H),3.72–3.69(m,1H),2. 94–2.90(m,1H),2.88–2.84(m,2H),2.65(t,J=14.0Hz,2H),2.49–2.48(m,1H) ,1.81–1.60(m,6H),1.54–1.45(m,3H),1.43–1.22(m,6H),1.12–1.06(m,2H). 13CNMR(150MHz,DMSO-d6)δ169.77,145.45,136.70,129.16,128.51,128.22,123.27,63.75,57.17,57.10,5 3.10,53.05,42.61,41.57,41.29,36.15,27.96,27.53,26.50,22.20,21.89,21.24,20.67.MSm / zcalcdfo ikB 25 H 33 N5O[M+H] + 420.27,found420.28.

[0147] Matrine-triazole derivative 4v: Synthesis of 14-[1-(benzyl)-1H-1,2,3-triazole-4-ethyl]-matrine:

[0148] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and (2-azidoethyl)benzene (compound 2v, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 285.5 mg of a yellow oily substance with a yield of 94.29%; melting point: 65.47-66.53°C.

[0149] 1 HNMR(600MHz,DMSO-d6)δ7.72(s,1H),7.26(t,J=7.4Hz,2H),7.20(t,J=7.3Hz,1H),7.16(d,J=7 .1Hz,2H),4.5(t,J=7.3Hz,2H),4.16(dd,J=12.2,4.2Hz,1H),3.79–3.76(m,1H),3.11(t,J=7.3H z,2H),2.99–2.93(m,2H),2.78–2.70(m,3H),2.51–2.44(m,2H),2.01(s,1H),1.88–1.75(m,4H) ,1.69–1.66(m,1H),1.62–1.56(m,2H),1.53–1.51(m,2H),1.48–1.41(m,2H),1.37–1.22(m,4H). 13CNMR(150MHz,DMSO-d6)δ169.94,144.95,138.18,129.13,128.82,126.99,123.21,63.90,57.16,57.09,53.14 ,50.72,42.45,41.68,41.61,36.29,36.14,28.03,27.44,26.57,22.28,21.84,21.23,20.69.MSm / zcalcdforC 26 H 35 N5O[M+H] + 434.29,found434.31.

[0150] Matrine-triazole derivative 4w: Synthesis of 14-[1-(1-methylnaphthalene)-1H-1,2,3-triazole-4-methyl]-matrine:

[0151] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 1-azidomethylnaphthalene (compound 2w, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 282.5 mg of a white crystalline solid with a yield of 86.15%; melting point: 66.46-67.09°C.

[0152] 1 HNMR(600MHz,DMSO-d6)δ8.12–8.10(m,1H),7.93–7.90(m,2H),7.53(s,1H),7.52–7.49(m,2H),7 .47–7.42(m,2H),5.95(q,J=15.0Hz,2H),3.95(dd,J=12.2,4.2Hz,1H),3.59–3.56(m,1H),2.97– 2.94(m,1H),2.80–2.72(m,2H),2.56(t,J=10.4Hz,2H),2.43(s,1H),1.70–1.58(m,3H),1.51–1. 40(m,5H),1.32–1.17(m,5H),1.13(d,J=13.0Hz,1H),0.84–0.80(m,2H),0.65(d,J=10.0Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.62,145.44,133.91,131.85,131.29,129.66,129.24,127.93,127.19,126.65,125.93,123.65,123.04 ,63.34,57.07,57.02,52.97,51.29,42.62,41.47,41.05,36.01,27.79,27.53,26.22,22.09,21.77,21.19,20.60.MSm / zcalcdforC 29 H 35 N5O[M+H] + 470.29,found470.30.

[0153] Matrine-triazole derivatives 4x: Synthesis of 14-[1-(2-methylnaphthalene)-1H-1,2,3-triazole-4-methyl]-matrine:

[0154] Using 14-(propargyl)matrine (3) (200 mg, 0.698 mmol) and 2-azidomethylnaphthalene (compound 2x, 1.047 mmol) as raw materials, the synthesis method was consistent with the synthesis of 14-[1-(4-fluorobenzyl)-1H-1,2,3-triazole-4-methyl]-matrine to obtain 241.7 mg of a white crystalline solid with a yield of 73.70%; melting point: 135.78-136.80°C.

[0155] 1 HNMR(600MHz,DMSO-d6)δ7.91–7.86(m,4H),7.65(s,1H),7.53–7.51(m,2H),7.39( d,J=8.4Hz,1H),5.67(q,J=14.6Hz,2H),3.99(dd,J=12.2,4.3Hz,1H),3.61–3.58( m,1H),3.08–3.05(m,1H),2.81–2.72(m,2H),2.54–2.48(m,3H),1.67–1.62(m,1H) ,1.55–1.36(m,6H),1.32–1.11(m,6H),1.05–0.83(m,3H),0.64(d,J=10.2Hz,1H). 13CNMR(150MHz,DMSO-d6)δ169.60,145.55,134.12,133.35,133.06,128.96,128.46,128.27,127.37,127.04,126.91,126.04,123.09 ,62.98,56.90,56.76,55.39,53.25,52.95,42.71,41.47,40.88,36.10,27.58,26.18,22.02,21.69,21.11,20.55.MSm / zcalcdforC 29 H 35 N5O[M+H] + 470.29,found470.28.

[0156] Application Examples

[0157] (1) The MTT method was used to investigate the in vitro antitumor activities of 24 triazole-containing matrine derivatives (4a-4x) against human gastric cancer cells SGC-7901, human breast cancer cells MCF-7, human liver cancer cells HepG2, and non-small cell lung cancer cells A549. The results are shown in Table 1.

[0158] Table 1 In vitro antitumor activity IC of matrine derivatives containing triazole structure 50 Value (N=3)

[0159]

[0160]

[0161] The anti-tumor activity of 24 synthesized matrine derivatives containing triazole structure (4a-4x) was tested by MTT method with hydroxycamptothecin as positive control drug, and their anti-tumor activity against four tumor cells SGC-7901, MCF-7, HepG2 and A549 was investigated. The results showed that most compounds had certain anti-tumor activity and were better than the lead compound matrine. Among them, 14-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine (4k) showed good anti-proliferative activity against the above cells, and had the best anti-tumor activity against liver cancer cell HepG2, with IC 50 The value was 16.80±0.49μM, so its effects on the cell cycle and apoptosis of liver cancer cells HepG2 were further studied.

[0162] The experimental results obtained by MTT method determined the effects of matrine derivative 4k on the cell cycle of liver cancer cells HepG2 at the concentrations of 8.5 μM, 17 μM and 34 μM respectively. Figure 1 As shown; compared with the blank group, it was found that with the increase of drug concentration, the proportion of cells in the G0 / G1 phase increased from 53.31% to 71.59%, the cells in the S phase decreased from 25.28% to 20.82%, and the cells in the G2 / M phase decreased from 23.41% to 7.59%. This shows that the matrine derivative 4k can affect the cell cycle distribution of HepG2 cells and block the liver cancer cells HepG2 in the G0 / G1 phase in a concentration-dependent manner. Figure 2 As shown, Figure 2 The results of cell cycle analysis of each group of cells (x±s, N=3, compared with the blank group: **P<0.01, ***P<0.001), statistical analysis and processing of the obtained data showed that the proportion of cells in the G0 / G1 phase of the drug-treated group was significantly different from that of the blank group. In summary, matrine derivative 4k may effectively block the liver cancer cell HepG2 in the G0 / G1 phase, and exert anti-tumor activity in a concentration-dependent manner.

[0163] (2) Effects of matrine derivatives containing triazole structures on cell apoptosis

[0164] The cell apoptosis was obtained by flow cytometry using the matrine derivative 4k at concentrations of 8.5 μM, 17 μM, and 34 μM. Figure 3 As shown in the figure, compared with the apoptosis of the blank group, the matrine derivative 4k at concentrations of 8.5μM, 17μM, and 34μM can effectively promote the apoptosis of HepG2 liver cancer cells, and the apoptosis rate is significantly increased. As the concentration of matrine derivative 4k increases, the apoptosis rate of HepG2 liver cancer cells also increases. The apoptosis rate of HepG2 liver cancer cells in the 34μM administration group is the highest. Figure 4 As shown, Figure 4 The analysis results of cell apoptosis in each group (x±s, N=3, compared with the blank group: ***P<0.001). Statistical analysis and processing of the obtained data showed that when the concentration of the matrine derivative 4k was 8.5μM, 17μM, and 34μM, it was analyzed and compared with the blank group, and there was a very significant statistical difference in the cell apoptosis rate.

[0165] The anti-tumor mechanism of 14-[1-(4-tert-butylbenzyl)-1H-1,2,3-triazole-4-methyl]-matrine (4k) may be that it effectively blocks the liver cancer cell HepG2 in the G0 / G1 phase and promotes cell apoptosis in a dose-dependent manner. The structure-activity relationship is summarized as follows:

[0166] (1) The introduction of F, Cl, and Br atoms can improve the antitumor activity of the lead compound matrine to a certain extent. Among them, the antitumor activity of the lead compound matrine increases with the introduction site of the Cl atom. The antitumor activity is in the order of para>meta>ortho.

[0167] (2) The longer the carbon number of the straight-chain alkane introduced on the benzene ring, the better its anti-tumor activity. The anti-tumor activity of the branched group introduced on the benzene ring is better than that of the straight-chain group; and the more carbon numbers of the branched chain, the better the anti-tumor activity.

[0168] (3) By comparing the derivatives containing -CF3 groups and the derivatives containing -O-CF3 groups, it can be found that the introduction of oxygen atoms can improve their inhibitory effect on tumor cells to a certain extent.

[0169] (4) Depending on the introduction site of the -CF3 group, its antitumor activity is in the order of meta > para > ortho.

[0170] (5) Introducing substituents on the benzene ring can effectively enhance the anti-tumor activity.

[0171] (6) In addition, the increase in the ClogP of the compound improves its lipid-water partition coefficient, increases the compound’s lipid solubility, facilitates transmembrane absorption, and further enhances its antitumor activity.

[0172] Therefore, the present invention adopts the above-mentioned matrine-triazole derivatives and their synthesis methods, takes matrine as the lead compound, and synthesizes a 1,2,3-triazole structural modification with anti-tumor activity for screening as a drug in the medical field.

[0173] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a matrine-triazole derivative, characterized in that: The following steps are involved: Step 1: In an ice bath and under nitrogen protection, lithium diisopropylamide was added to a round-bottom flask and stirred at a uniform speed. Matrine was weighed and dissolved in 80 mL of anhydrous tetrahydrofuran and slowly added to the reaction system. After stirring for 1 h, 3-bromopropyne was weighed and slowly added to the reaction system. The mixture was stirred at room temperature for 5 h. Methanol:ethyl acetate=1:15 was used as the developing solvent. After TLC detection of the reaction was completed, the reaction system was closed and the reaction apparatus was dismantled. 150 mL of saturated NaHCO3 solution was added to quench lithium diisopropylamide. The mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous Na2SO4, filtered, and rotary evaporated to obtain a yellow oily crude product. The crude product was purified by silica gel column chromatography with an eluent polarity of methanol:ethyl acetate=1:30 to obtain a white flocculent solid, i.e. 14-(propargyl)matrine (3); Step 2: The 14-(propargyl)matrine (3) prepared in step 1 was dissolved in 3 mL of toluene solution, and compound A and 0.1396 mmol of cuprous thiophene-2-carboxylate were added in sequence. The mixture was stirred at a constant speed and reacted at room temperature for 3 h. The reaction progress was monitored by TLC plate. The developing solvent polarity was methanol: dichloromethane = 1:

15. After the reaction was completed, water and dichloromethane were added for extraction. The organic phases were combined, filtered, and distilled under reduced pressure to obtain a green solid crude product. The product was purified by silica gel column chromatography. The eluent polarity was methanol: dichloromethane = 1:30 to obtain a white powdery solid, which was the matrine-triazole derivative.

2. The method for synthesizing the matrine-triazole derivative according to claim 1, characterized in that: In step 1, the amount of lithium diisopropylamide added is 12 mL, the amount of matrine added is 20 mmol, and the amount of 3-bromopropyne added is 4 times that of matrine.

3. The method for synthesizing the matrine-triazole derivative according to claim 1, characterized in that: In step 2, the amount of 14-(propargyl)matrine (3) added is 0.698 mmol, and the amount of compound A added is 1.047 mmol.

4. The method for synthesizing the matrine-triazole derivative according to claim 1, characterized in that: In step 2, the synthesis method of compound A is: Take trimethylsilane and place it in a 50mL round-bottom flask, add 8mL of hexamethylphosphoric acid triamide solution, drop compound B, and keep at 70°C overnight. Use petroleum ether as the developing solvent and monitor the reaction on a TLC plate. After the reaction is completed, cool to room temperature, remove the solvent by distillation under reduced pressure, add 100mL of water and dichloromethane to repeatedly extract the reaction system, combine the organic phases, dry over anhydrous Na2SO4, filter, rotary evaporate, and purify by silica gel column chromatography. The eluent polarity is ethyl acetate: petroleum ether = 1:100 to obtain a colorless transparent liquid.

5. The method for synthesizing the matrine-triazole derivative according to claim 4, characterized in that: The compound B is one of 4-fluorobenzyl bromide, 3-fluorobenzyl bromide, 2-fluorobenzyl bromide, 4-chlorobenzyl bromide, 3-chlorobenzyl bromide, 2-chlorobenzyl bromide, 4-bromobenzyl bromide, 3-bromobenzyl bromide, 2-bromobenzyl bromide, 4-methylbenzyl bromide, 4-tert-butylbenzyl bromide, 4-propylbenzyl bromide, 4-isopropylbenzyl bromide, 4-trifluoromethylbenzyl bromide, 3-trifluoromethylbenzyl bromide, 2-trifluoromethylbenzyl bromide, 4-trifluoromethoxybenzyl bromide, 3-trifluoromethoxybenzyl bromide, 3-benzyloxybenzyl bromide, 4-bromomethylbiphenyl, benzyl bromide, 1-bromomethylnaphthalene, and 2-(bromomethyl)naphthalene.

6. The method for synthesizing the matrine-triazole derivative according to claim 4, characterized in that: The amount of the azidotrimethylsilane added was 7.9 mmol, and the amount of the compound B added was 3.8 mmol.

7. A matrine-triazole derivative synthesized according to the synthesis method according to any one of claims 1 to 6.

8. The matrine-triazole derivative according to claim 7, characterized in that: The structural formula of the matrine-triazole derivative is as follows: The R group is one of 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-CH3, 4-C(CH3)3, 4-CH2CH2CH3, 4-CH(CH3)2, 4-CF3, 3-CF3, 2-CF3, 4-O-CF3, 3-O-CF3, 3-O-CH2-C6H6, 4-C6H6, and H.

Images